The present invention relates generally to the infection of target cells by HIV-1, HIV-2 and SIV and more particularly to agents identified herein that mediate the entry of retroviruses into such target cells, and to the diagnostic and therapeutic uses to which such agents may be put. Furthermore, the present invention relates to methods of identifying agents that can modulate the expression and/or function of Bonzo/STRL33. Such agents can be used to either treat inflamation, or alternatively, to enhance the immune response.
The human immunodeficiency viruses infect CD4+ macrophages and T helper cells. Although HIV-1 entry requires cell surface expression of CD4, to which the viral envelope glycoproteins bind, several studies have suggested that it is not sufficient for fusion of the viral envelope to the cellular plasma membrane. Early studies have shown that while human cells expressing a transfected CD4 gene were permissive for virus entry, murine cells expressing human CD4 were not. These findings led to the suggestion that there is a species-specific cell surface cofactor required in addition to CD4 for HIV-1 entry. Subsequent studies have shown that strains of HIV-1 that had been adapted for growth in transformed T-cell lines (T-tropic strains) could not infect primary monocytes or macrophages; in contrast, primary viral strains were found to infect monocytes and macrophages, but not transformed T cell lines. This difference in tropism was found to be a consequence of specific sequence differences in the gp120 subunit of the envelope glycoprotein, suggesting that multiple cell type-specific cofactors may be required for entry in addition to CD4.
The nature of the cofactors required for HIV entry proved elusive until it was recently discovered that the principal receptor for entry of macrophage-tropic (M-tropic) HIV-1 strains was CCR5, whereas the principal receptor for entry of T-cell line-tropic (T-tropic) strains was CXCR4. On the other hand, both M-tropic and T-tropic strains of simian immunodeficiency virus (SIV) can be mediated by CCR5, but not CXCR4 [Chew et al., J. Virol, 71:2705-2714 (1997); Marcon et al., J. Virol, 71:2522-2527 (1997); and Edinger et al., Proc. Natl. Acad. Sci. USA, 94:4005-4010 (1997)]. More importantly, SIV strains were also found to infect CD4+ cells that lack CCR5 [Chen et al., 1997, supra; and Edinger et al., 1997, supra].
In humans, CCR5-tropic viruses are primarily involved in transmission, while viruses with broader tropism, particularly for CXCR4, emerge during progression to immunodeficiency [Fauci, Nature, 384:529-534 (1996)]. It is not yet known whether appearance of CXCR4-tropic viruses is a consequence or the cause of immune system decline. Insight into this key problem of virus evolution is likely to require experimental manipulation in animal models. Infection of non-human primates with SIV is currently the only good animal model for studying pathogenesis of the immunodeficiency viruses [Desrosiers, Annu Rev Immunol, 8:557-578 (1990)]. Moreover, different species of non-human primates vary widely in their responses to SIV infection. For example, Rhesus macaques succumb to immunodeficiency that closely resembles AIDS in humans, but sooty mangabeys and African green monkeys can sustain infection with little evidence of immune system damage [Kestler, Science, 248:1109-1112 (1990)]. These interspecies differences provide important clues for understanding and combating disease progression in HIV-infected humans.
Therefore, there is a need to identify and structurally characterize translocation promoting agents other than CCR5 and CXCR4 that function in conjunction with CD4 during SIV and/or HIV infection of human cells as well in the subsequent disease progression. Further, there is a need to determine the specific strains of the retroviruses that can use such translocation promoting agents as alternatives to CXCR4 and CCR5. In addition, there is a need to provide methods of identifying drugs that can interfere with retroviral infection by hindering the interaction of CD4, the various translocation promoting agents and the retroviral envelope glycoproteins.
The citation of any reference herein should not be construed as an admission that such reference is available as xe2x80x9cPrior Artxe2x80x9d to the instant application.
The present invention provides an expression cloning strategy to identify SIV receptors which may play a role in human acquired immunodeficiency disease. Two particular nucleic acids encoding two members of the 7-transmembrane G-protein coupled receptor family were identified and isolated by the methods described herein. These SIV receptors were also found to be used by particular strains of HIV-2 and M-tropic HIV-1.
One aspect of the present invention provides an isolated nucleic acid encoding a translocation promoting agent that is substantially homologous to SEQ ID NO:1. In a preferred embodiment of this type the nucleic acid is obtained from a primate. In one such embodiment the nucleic acid encodes a translocation promoting agent that is substantially homologous to SEQ ID NO:3. In another such embodiment the isolated nucleic acid encodes a translocation promoting agent that is substantially homologous to SEQ ID NO:5. In the most preferred embodiment the isolated nucleic acid encodes a translocation promoting agent isolated from a human source.
The present invention also includes nucleic acid primers and/or probes for all of the nucleic acids of the present invention. In addition, the nucleic acids of the present invention may be RNA, or single or doubled stranded DNA, including recombinant DNA.
The present invention also includes an isolated nucleic acid which encodes a translocation promoting agent having the amino acid sequence of SEQ ID NO:2 having one or more conservative substitutions. In a related embodiment the isolated nucleic acid encodes a translocating promoting agent having the amino acid sequence of SEQ ID NO:2. In a preferred embodiment of this type the isolated nucleic acid has a nucleic acid sequence of SEQ ID NO:1.
The present invention also includes an isolated nucleic acid encoding a translocation promoting agent having the amino acid sequence of SEQ ID NO:4 having one or more conservative substitutions. In a related embodiment the isolated nucleic acid encodes a translocation promoting agent having the amino acid sequence of SEQ ID NO:4. In a preferred embodiment of this type the isolated nucleic acid has the nucleic acid sequence of SEQ ID NO:3.
The present invention also includes an isolated nucleic acid encoding a translocation promoting agent having the amino acid sequence of SEQ ID NO:6 having one or more conservative substitutions. In a related embodiment the isolated nucleic acid encodes a translocating promoting agent having the amino acid sequence of SEQ ID NO:6. In a preferred embodiment of this type the isolated nucleic acid has the nucleic acid sequence of SEQ ID NO:5.
The present invention also includes an isolated nucleic acid encoding a translocation promoting agent having the amino acid sequence of SEQ ID NO:10 having one or more conservative substitutions. In a related embodiment the isolated nucleic acid encodes a translocating promoting agent having the amino acid sequence of SEQ ID NO:10. In a preferred embodiment of this type the isolated nucleic acid has the nucleic acid sequence of SEQ ID NO:9.
The present invention also includes an isolated nucleic acid encoding a translocation promoting agent having the amino acid sequence of SEQ ID NO:12 having one or more conservative substitutions. In a related embodiment the isolated nucleic acid encodes a translocating promoting agent having the amino acid sequence of SEQ ID NO:12. In a preferred embodiment of this type the isolated nucleic acid has the nucleic acid sequence of SEQ ID NO:11.
The present invention also includes nucleic acids which contain 18 or more nucleotides that hybridize to a nucleic acid having the nucleotide sequence of SEQ ID NO:1 under standard conditions.
The present invention also includes nucleic acids which contain 18 or more nucleotides that hybridize to a nucleic acid having the nucleotide sequence of SEQ ID NO:3 under standard conditions.
The present invention also includes nucleic acids which contain 18 or more nucleotides that hybridize to a nucleic acid having the nucleotide sequence of SEQ ID NO:5 under standard conditions.
The present invention also includes nucleic acids which contain 18 or more nucleotides that hybridize to a nucleic acid having the nucleotide sequence of SEQ ID NO:9 under standard conditions.
The present invention also includes nucleic acids which contain 18 or more nucleotides that hybridize to a nucleic acid having the nucleotide sequence of SEQ ID NO:11 under standard conditions.
The present invention also provides nucleic acids encoding fusion proteins containing the translocation promoting agents of the present invention and a peptide tag or protein. Such fusion proteins can include, for example Bonzo fused with green fluorescent protein, or Bonzo fused with glutathione-s-transferase.
Also included in the present invention are DNA constructs comprising the isolated nucleic acids of the present invention, that are operatively linked to an expression control sequence. In a preferred embodiment of this type the nucleic acid has the nucleotide sequence of SEQ ID NO:1.
The present invention also includes methods of using the DNA constructs of the present invention to express the translocation promoting agent which they encode. One such embodiment comprises introducing the construct into a host cell and expressing the translocation promoting agent in that host cell. In a preferred embodiment of this type the method includes purifying the translocation promoting agent that was expressed.
The present invention also includes unicellular host cells transformed with the DNA constructs of the present invention. In one preferred embodiment of this type the unicellular host is a primate cell. In a more preferred embodiment the unicellular host is a human cell.
Another aspect of the present invention provides an isolated translocation promoting agent having the amino acid sequence that is substantially homologous to SEQ ID NO:2. In one such embodiment the translocation promoting agent has the amino acid sequence of SEQ ID NO:2 having one or more conservative substitutions. In a preferred embodiment the translocation promoting agent has the amino acid sequence of SEQ ID NO:2.
Another aspect of the present invention provides an isolated translocation promoting agent having the amino acid sequence that is substantially homologous to SEQ ID NO:4. In one such embodiment the translocation promoting agent has the amino acid sequence of SEQ ID NO:4 having one or more conservative substitutions. In a preferred embodiment the translocation promoting agent has the amino acid sequence of SEQ ID NO:4.
Another aspect of the present invention provides an isolated translocation promoting agent having the amino acid sequence that is substantially homologous to SEQ ID NO:6. In one such embodiment the translocation promoting agent has the amino acid sequence of SEQ ID NO:6 having one or more conservative substitutions. In a preferred embodiment the translocation promoting agent has the amino acid sequence of SEQ ID NO:6.
Another aspect of the present invention provides an isolated translocation promoting agent having the amino acid sequence that is substantially homologous to SEQ ID NO:10. In one such embodiment the translocation promoting agent has the amino acid sequence of SEQ ID NO:10 having one or more conservative substitutions. In a preferred embodiment the translocation promoting agent has the amino acid sequence of SEQ ID NO:10.
Another aspect of the present invention provides an isolated translocation promoting agent having the amino acid sequence that is substantially homologous to SEQ ID NO:12. In one such embodiment the translocation promoting agent has the amino acid sequence of SEQ ID NO:12 having one or more conservative substitutions. In a preferred embodiment the translocation promoting agent has the amino acid sequence of SEQ ID NO:12.
Peptide fragments of all the translocation promoting agents of the present invention are also part of the present invention. Such fragments can be generated by treatment with proteolytic enzymes and the like.
The present invention also provides antibodies to the translocation promoting agents of the present invention. In one embodiment of this type the antibody is to the translocation promoting agent having the amino acid sequence of SEQ ID NO:2 having one or more conservative substitutions. In a preferred embodiment of this type the antibody is to the translocation promoting agent having the amino acid sequence of SEQ ID NO:2. In another embodiment of this type the antibody is to the translocation promoting agent having the amino acid sequence of SEQ ID NO:4 having one or more conservative substitutions. In a preferred embodiment of this type the antibody is to the translocation promoting agent having the amino acid sequence of SEQ ID NO:4. In an alternative embodiment of this type the antibody is to the translocation promoting agent having the amino acid sequence of SEQ ID NO:6 having one or more conservative substitutions. In a preferred embodiment of this type the antibody is to the translocation promoting agent having the amino acid sequence of SEQ ID NO:6. In yet another embodiment of this type the antibody is to the translocation promoting agent having the amino acid sequence of SEQ ID NO:10 having one or more conservative substitutions. In a preferred embodiment of this type the antibody is to the translocation promoting agent having the amino acid sequence of SEQ ID NO:10. In still another embodiment of this type the antibody is to the translocation promoting agent having the amino acid sequence of SEQ ID NO:12 having one or more conservative substitutions. In a preferred embodiment of this type the antibody is to the translocation promoting agent having the amino acid sequence of SEQ ID NO:12.
In a preferred embodiment the antibody is a monoclonal antibody and/or a chimeric antibody. The present invention also includes an immortal cell line that produces a monoclonal antibody of the present invention.
The present invention also provides a mammalian cell that expresses human CD4 and is transfected with a vector encoding Bonzo. In one such embodiment Bonzo is a human Bonzo. In a preferred embodiment the human Bonzo has an amino acid sequence of SEQ ID NO:2.
In another embodiment a mammalian cell which expresses CD4, but expresses low levels or no CXCR4 and CCR5, in the absence of transduction with a vector encoding CXCR4 and/or CCR5, is transfected with a vector encoding human Bonzo. In an alternative embodiment, the mammalian cell further comprises a vector encoding one or more translocation promoting agents such as CCR5, CXCR4, CCR2b, CCR3, and BOB.
A related aspect of the invention is a mammalian cell that is transfected with a vector encoding human CD4 and a vector encoding human or primate BOB. In one embodiment the primate BOB has the amino acid sequence of SEQ ID NO:10 or 12. In another embodiment the human BOB has the amino acid sequence of SEQ ID NO:8.
In another embodiment a mammalian cell which expresses CD4, but expresses low levels or no CXCR4 and CCR5, in the absence of transduction with a vector encoding CXCR4 and/or CCR5, is transfected with a vector encoding human BOB. In an alternative embodiment, the mammalian cell further comprises a vector encoding one or more translocation promoting agents such as CCR5, CXCR4, CCR2b, CCR3, and Bonzo.
The present invention also includes the mammalian cells of the present invention attached to solid support matrices. In preferred embodiments of these type the mammalian cell is a human cell.
Another aspect of the present invention is a transgenic non-human mammal comprising a DNA construct containing a human CD4 gene and DNA construct containing a human translocation promoting agent such as BOB or Bonzo. In a preferred embodiment the transgenic non-human mammal further comprises one or more DNA constructs which contain an alternative human translocation promoting agent such as CCR5, CXCR4, CCR2b, and/or CCR3. In a preferred embodiment the transgenic non-human mammal is a mouse.
The present invention further provides a method of identifying a nucleic acid that encodes a human translocation promoting agent which in conjunction with CD4 serves as a receptor for the entry into a cell of a virus having a specific viral envelope glycoprotein. One such method includes transfecting a mammalian cell with a viral vector containing a human cDNA with a flanking-viral insert. Preferably the mammalian cell expresses human CD4 and a known human translocation promoting agent, such as CCR5, but does not express the human translocation promoting agent encoded by the human cDNA which is obtained from a human cDNA library. Next the mammalian cell is transfected with a first selectable viral vector pseudotyped with the specific viral envelope glycoprotein. In this case the first selectable viral vector encodes a first selectable marker. The mammalian cell is then identified by expressing the first selectable marker. The identified mammalian cell is next transfected with a second selectable viral vector that is pseudotyped with a paticular viral envelope glycoprotein. The second selectable viral vector encodes a second selectable marker, and the known human translocation promoting agent can serve in conjunction with CD4 as a receptor for entry of a virus having the particular envelope glycoprotein. An identified mammalian cell is then selected which does not express the second selectable marker. DNA is then extracted from the selected mammalian cell and amplified by PCR using primers for the flanking insert from the viral vectors. In this way a nucleic acid encoding a human translocation promoting agent that can serve in conjunction with CD4 as a receptor for entry of virus having the specific viral envelope glycoprotein is identified.
In one such embodiment the first selectable viral vector is a selectable replication-defective virus. In a preferred embodiment of this type the first selectable viral vector is an HIV-pseudotyped vector. In another embodiment of this type the second selectable viral vector is a selectable replication-defective virus. In a preferred embodiment of this type the second selectable viral vector is an HIV-pseudotyped vector. In a more preferred embodiment both the first selectable viral vector and the second selectable viral vector are HIV-pseudotyped vectors.
In another embodiment of this type the viral vector containing the human cDNA is obtained from the supernatant of BOSC23 packaging cells after subcloning the human cDNA library in the retrovirus pMX and transfecting the human cDNA library into the BOSC23 packaging cells. In another embodiment the mammalian cell is 3T3.CD4. In yet another embodiment the first selectable marker confers antibiotic resistance to the cell. In a preferred embodiment of this type the antibiotic is puromycin and the identification of the mammalian cell expressing the first selectable marker is performed by administering puromycin to the cells and identifying cells that are puromycin resistant. In another embodiment the first selectable marker is green fluorescent protein. In a related embodiment the second selectable marker is green fluorescent protein. In another embodiment of this type the first selectable marker is luciferase. In still another embodiment of this type the second selectable marker is luciferase.
The known translocation promoting agent used in these methods can be any translocating promoting agent known including CCR5, CXCR4, CCR2b, CCR3, Bonzo, and BOB. In a preferred embodiment the known translocation promoting agent is CCR5 and the particular viral envelope glycoprotein is JRFL.
The present invention also includes assays for selecting for a suspected therapeutic agent for possible use in the treatment of AIDS with the use of one of the cells of the present invention. In one particular embodiment the cell is a mammalian cell that expresses human CD4 and is transfected with a vector encoding human Bonzo. In another particular embodiment the mammalian cell is transfected with a vector encoding human CD4 and a vector encoding a human translocation promoting agent such as Bonzo or BOB. In preferred embodiments of this type Bonzo and BOB are human Bonzo and human BOB.
One such method for selecting a suspected therapeutic agent for possible use in the treatment of AIDS comprises administering a potential therapeutic agent to the cell. The cell is next infected with a virus pseudotyped with an HIV envelope glycoprotein.
This is followed by measuring the ability of the cell to resist the infection. Finally the potential therapeutic agent is selected when the measured ability of the cell to resist the infection is statistically greater in the presence of the potential therapeutic agent than in the absence of the potential therapeutic agent. In this case the selected potential therapeutic agent is a suspected therapeutic agent. In a preferred embodiment of this type the virus contains a marker protein and measuring the ability of the cell to resist the infection is performed by detecting the amount of marker protein expressed in the cell. In this case the measured ability of the cell to resist the infection is inversely proportional to the amount of marker protein detected. In a more preferred embodiment of this type the marker protein is either luciferase or green fluorescent protein.
The present invention also includes an assay for selecting a plausible therapeutic agent for possible use in the treatment of AIDS with the use of a transgenic non-human mammal that comprises a DNA construct containing a human CD4 gene and a DNA construct containing either human Bonzo or human BOB. One such method comprises administering a suspected therapeutic agent to the transgenic non-human mammal. Then the transgenic non-human mammal is infected with a virus pseudotyped with an HIV envelope glycoprotein. The ability of the transgenic non-human mammal to resist infection is then measured. The suspected therapeutic agent is selected when the measured ability of the transgenic non-human mammal to resist the infection is statistically greater in the presence of the suspected therapeutic agent than in the absence of the therapeutic agent. In this case the selected therapeutic agent is a plausible therapeutic agent.
The present invention also includes a method of filtering a biological fluid to remove and/or isolate a virus expressing an HIV envelope glycoprotein that binds with CD4 and Bonzo and/or BOB wherein the biological fluid is passed through a mammalian cell which expresses human CD4 and human Bonzo and/or human BOB and is attached to a solid support matrix. In one such embodiment, the mammalian cell is transfected with a vector encoding human CD4 and a vector encoding human Bonzo and/or a vector encoding human BOB.
In yet another aspect of the present invention a method is provided for identifying a ligand for human Bonzo. In one such assay a potential ligand is contacted with a mammalian cell that expresses human Bonzo and CD4, but the mammalian cell does not express CCR5, CXCR4, CCR2b, CCR3, and BOB. Next the mammalian cell is transfected with a selectable replication defective virus (such as HIV) pseudotyped with a specific viral envelope glycoprotein. In this case Bonzo in conjunction with CD4 serves as a receptor for entry into a cell of a virus having the specific viral envelope glycoprotein. Finally the marker protein is detected and a ligand is selected when the amount of marker protein detected is less than that detected when the transfection of the mammalian cells with the selectable replication-defective virus is performed without the prior contacting of a potential ligand with the mammalian cell. In a preferred embodiment of this type the marker protein is either luciferase or green fluorescent protein. In another preferred embodiment the method includes contacting the selected ligand with purified human Bonzo and then detecting the binding of that ligand to the purified human Bonzo. In this case a ligand is identified by its binding to the purified human Bonzo. In a more preferred embodiment, the ligand binds to the purified human Bonzo under standard physiological conditions (e.g. 100 mM NaCl pH7.4, at 37xc2x0 C.) and has a KD of less than 10xe2x88x926 Molar.
In yet another aspect of the present invention a method is provided for identifying a ligand for human BOB. In one such assay a potential ligand is contacted with a mammalian cell that expresses human BOB and CD4, but the mammalian cell does not express CCR5, CXCR4, CCR2b, CCR3, and Bonzo. Next the mammalian cell is transfected with a selectable replication defective virus (such as HIV) pseudotyped with a specific viral envelope glycoprotein. In this case BOB in conjunction with CD4 serves as a receptor for entry into a cell of a virus having the specific viral envelope glycoprotein. Finally the marker protein is detected and a ligand is selected when the amount of marker protein detected is less than that detected when the transfection of the mammalian cells with the selectable replication-defective virus is performed without the prior contacting of a potential ligand with the mammalian cell. In a preferred embodiment of this type the marker protein is either luciferase or green fluorescent protein. In another preferred embodiment the method includes contacting the selected ligand which was selected with purified human BOB and then detecting the binding of that ligand to the purified human BOB. In this case a ligand is identified by binding to the purified human BOB. In a more preferred embodiment, the ligand binds to the purified human BOB under standard physiological conditions (e.g. 100 mM NaCl pH7.4, at 37xc2x0 C.) and has a KD of less than 10xe2x88x926 Molar.
The present invention further provides methods of identifying agents that can modulate the expression and/or function of Bonzo/STRL33. In one such method, the agent can be selected for enhancing the immune response to a specific pathogen and/or can be selected for enhancing the immune response against a specific vaccine. One embodiment comprises contacting an agent with a cell that encodes Bonzo/STRL33 and then determining (e.g., measuring) the amount of Bonzo/STRL33 expressed by a cell in the presence of the agent. An agent is identified as an agent that can enhance the immune response to a specific pathogen and/or against a specific vaccine when the amount of expression of Bonzo/STRL33 increases in the presence of the agent relative to in the absence of the agent. In one particular embodiment, determining the amount of Bonzo/STRL33 expressed by the cell is performed with an antibody raised against Bonzo/STRL33. In another embodiment determining the amount of Bonzo/STRL33 expressed by the cell is performed by PCR.
In another method, an agent can be selected for enhancing the immune response to a specific pathogen and/or can be selected for enhancing the immune response against a specific vaccine by contacting an agent with a cell that normally encodes Bonzo/STRL33, but in which the coding sequence for Bonzo/STRL33 has been replaced by a coding sequence for a reporter gene. The amount of the reporter gene expressed by the cell in the presence of the agent is then determined (e.g., measured). An agent is identified as an agent that can enhance the immune response to a specific pathogen and/or against a specific vaccine when the amount of the reporter gene expressed by the cell increases in the presence of the agent relative to in the absence of the agent. In a particular embodiment the coding sequence for the reporter gene encodes green fluorescent protein. In another embodiment, the coding sequence for the reporter gene encodes luciferase.
The present invention also provides the agents obtained by such methods. Preferably, the agent is a small organic molecule. The present invention further provides methods of enhancing the immune response for a specific pathogen or to enhance the effect of a specific vaccine that comprises administering an agent identified by a method of the present invention to an animal subject. Preferably the animal subject is a human.
The present invention also provides methods of identifying agents that can inhibit the recruitment of memory cells. One such embodiment comprises contacting an agent with a cell that encodes Bonzo/STRL33 and then determining (e.g., measuring) the amount of Bonzo/STRL33 expressed by a cell in the presence of the agent. An agent is identified as an agent that can inhibit the recruitment of memory cells when the amount of expression of Bonzo/STRL33 decreases in the presence of the agent relative to in the absence of the agent. In one particular embodiment, determining the amount of Bonzo/STRL33 expressed by the cell is performed with an antibody raised against Bonzo/STRL33. In another embodiment determining the amount of Bonzo/STRL33 expressed by the cell is performed by PCR.
In another method, the agent can be selected for inhibiting the recruitment of memory cells by contacting an agent with a cell that normally encodes Bonzo/STRL33, but in which the coding sequence for Bonzo/STRL33 has been replaced by a coding sequence for a reporter gene. The amount of the reporter gene expressed by the cell in the presence of the agent is then determined (e.g., measured). An agent is identified as an agent that can inhibit the recruitment of memory cells when the amount of expression of Bonzo/STRL33 decreases in the presence of the agent relative to in the absence of the agent. In a particular embodiment the coding sequence for the reporter gene encodes green fluorescent protein. In another embodiment, the coding sequence for the reporter gene encodes luciferase.
The present invention also provides the agents obtained by such methods. Preferably, the agent is a small organic molecule. The present invention further provides methods of treating inflammation comprising administering an agent identified by a method of the present invention to an animal subject in need of such treatment. Preferably the animal subject is a human.
The present invention also provides methods of enhancing the immune response for a specific pathogen and/or to enhance the effect of a specific vaccine that comprises administering to an animal subject an agent that causes an increase in Bonzo/STRL 33 expression and/or function. In a preferred embodiment of this type the animal subject is a human.
The present invention further provides methods of treating inflammation that comprise administering to an animal subject in need of such treatment an agent that causes a decrease in Bonzo/STRL 33 expression and/or function. In a preferred embodiment of this type the animal subject is a human. In a particular embodiment the agent is an antisense nucleic acid to the Bonzo/STRL 33 transcript. In another such embodiment the agent is an antibody to the Bonzo/STRL 33 protein. In still another embodiment the agent is a particular compound that blocks the function of Bonzo/STRL 33 protein. In a particular embodiment of this type the agent is a small organic compound that binds to the Bonzo/STRL 33 protein and thereby inhibits its function.
These and other aspects of the present invention will be better appreciated by reference to the following drawings and Detailed Description.